The long-term goal of this project is to develop C. elegans as a model system for studying telomerase and telomere biology. Telomerase maintains chromosome integrity by adding de novo telomere repeats to chromosome termini. Most human somatic cells lack telomerase and display telomere erosion as they proliferate, which can lead to critical telomere shortening and senescence. We propose to study a promiscuous DNA replication process that may promote large-scale subtelomeric genome duplications at critically shortened telomeres. This process may be broadly relevant in genome evolution and could contribute to tumorigenesis. We hypothesize that telomere dysfunction can activate one or more stress response pathways that 1) may trigger systemic effects on organismal physiology that could contribute to aging or age-related diseases, 2) may promote survival in the absence of telomerase via a telomerase-independent telomere replication pathway termed Alternative Lengthening of Telomeres (ALT). A long-standing hypothesis in the field of chromosome biology is that aspects of genome evolution could be an orchestrated response to stress. The proposed studies will address this hypothesis in the context of telomere biology using a metazoan model system where a variety of conserved stress response pathways have been well characterized and where powerful genetic, cell biology and genomic tools are available: the nematode C. elegans. !